Pulmonary edema in infants and children
Hugh O’Brodovich
Purpose of review
To provide an overview of the pathogenesis of pulmonary
edema and describe recent discoveries related to the
clearance of airspace fluid and potential new therapies for
this life-threatening disorder.
Recent findings
It is clinically important to determine the mechanisms
responsible for the clearance of fluid from the airspaces. At
birth inadequate clearance of fetal lung liquid is one of the
two mechanisms leading to respiratory distress syndrome
in the premature infant. Adults with heart failure or adult
respiratory distress syndrome survive when they had active
absorption of airspace fluid, yet have greater morbidity
or die when they show no evidence of active fluid
clearance. Humans who are susceptible to high-altitude
pulmonary edema have less ability to actively transport
fluid across their respiratory epithelium.
Summary
New approaches to increase the active clearance of
fluid from the airspaces, combined with further
improvements in the intensive care and monitoring of
patients with serious illnesses, will lead to improved care
for patients with lung diseases characterized by
increased lung water content.
Keywords
pulmonary edema, epithelial active Na+ transport,
high-altitude pulmonary edema, respiratory distress
syndrome, acute respiratory distress syndrome
—384. ª 2005 Lippincott Williams & Wilkins.
Curr Opin Pediatr 17:381—
Department of Paediatrics and Lung Biology Programme at The Hospital for Sick
Children and the Departments of Paediatrics and Physiology at the University of
Toronto, Toronto, Ontario, Canada
Correspondence to Hugh O’Brodovich, MD, FRCP(C), Hospital for Sick Children,
555 University Avenue, Toronto, Ontario, Canada M5G-1X8
Tel: 416 813 6122; fax: 416 813 7479; e-mail: hugh.obrodovich@sickkids.ca
Current Opinion in Pediatrics 2005, 17:381—
—384
Abbreviations
AFC alveolar fluid clearance
ALI acute lung injury
ARDS acute respiratory distress syndrome
CHF congestive heart failure
V/Q ventilation to perfusion ratio
ª 2005 Lippincott Williams & Wilkins.
1040-8703
Introduction
Much study has occurred over many decades on the path-
ogenic mechanisms producing pulmonary edema. In con-
trast, only recently has it been recognized that it is equally
important to determine the mechanisms responsible for
the clearance of alveolar pulmonary edema. If the lungs
cannot clear the airspace fluid there will be an unaccept-
ably low oxygen level in the blood, pulmonary vascular re-
sistance will remain elevated, and there will continue to
be an increased work of breathing. This airspace fluid
clearance is important to the patient as it has been shown
that adults with congestive heart failure (CHF) or acute
respiratory distress syndrome (ARDS) survive when they
have active absorption of airspace fluid, yet die when they
show no evidence of active fluid clearance. If we can find
discover an approach that would reliably and safely aug-
ment the rate of fluid clearance from the lung’s airspaces,
we could have a significant impact on the many lung dis-
eases that are characterized by increased lung water
content.
Anatomic considerations
In contrast to the systemic circulation, where the vast ma-
jority of fluid moves out of the circulation within the capil-
laries, fluid exchange occurs across the lung’s pulmonary
arterioles, capillaries, and venules. Under normal condi-
tions fluid leaves these microvessels, enters the intersti-
tial space, and then is cleared by the lymphatics. In
a significant portion of the alveolus, the basement mem-
branes of the capillary endothelium and the alveolar epi-
thelium are fused together with no additional space
between them; this helps preserve gas exchange even
when there is increased movement of fluid out of the lung
microvasculature with resultant interstitial pulmonary
edema. Only when the alveoli themselves are filled with
fluid is there a significant impairment of oxygen uptake
and carbon dioxide excretion.
The alveolar epithelial membrane contains much tighter
intercellular junctions than does the capillary endothelial
membrane; their effective molecular radii are approxi-
mately 4 and 40 Å, respectively. This is a very important
difference as it results in small ions being osmotically ac-
tive across the epithelial, but not endothelial, membrane
whereas only the very much larger proteins are osmotically
active across the endothelial membranes. Thus total os-
motic pressure is important when discussing transepithe-
lial fluid movement but it is only the protein-derived
osmotic pressure, or oncotic pressure, that acts across
the endothelium.
381
382 Pulmonology
The lung has two main compartments that can accommo-
date excess fluid. The adult lung can hold a few hundred
milliliters in its interstitial compartment whereas the al-
veolar space can accommodate several liters of fluid. This ana-
tomic difference, in part, explains why interstitial edema
may resolve quickly whereas alveolar edema takes signif-
icantly longer periods.
Juxtacapillary receptors are distributed throughout the
lung’s interstitium and are stimulated by the presence of
edema. They induce an increase in respiratory rate and
their continued activation is responsible, in large part, for
the continued tachypneoa seen in pulmonary edema even
though hypoxaemia has been corrected through the use of
supplemental oxygen and positive airway pressure.
Pathophysiologic mechanisms leading to
pulmonary edema
Lung edema, defined as an increase in lung water content,
occurs when the rate of fluid movement out of the lung’s
microvasculature exceeds the capacity of the lymphatics
to clear the fluid from the lung’s interstitium.
Although many diseases cause pulmonary edema, they do
so by only one of two processes, or a combination of these
two processes. Most frequently there is an increase in fluid
movement out of the microvasculature from an increase in
transvascular pressure gradients. Two examples are CHF,
in which there is an abnormally high intravascular pressure
with fluid being squeezed out of the vessels, and reexpan-
sion pulmonary edema, in which markedly negative inter-
stitial pressures ‘suck’ the fluid out of the blood vessels.
The second process, which occurs much less frequently,
involves the lung’s blood vessels becoming abnormally
leaky, i.e., a high permeability to water and solutes, and
intravascular fluid easily permeates into the lung’s inter-
stitium and airspaces. The clinical correlate is the acute
lung injury (ALI) – ‘adult’ respiratory distress syndrome
(ARDS) – that can occur at any age.
There are many different disorders associated with pul-
monary edema, only some of which are listed in Table 1.
Some are predominately, if not exclusively, due to one of
the above processes (indicated in Table 1 by ++++)
whereas others are associated with a contribution from
the other process (indicated in Table 1 by ++) that can
lead to edema formation. The underlying mechanisms are
discussed in greater detail elsewhere [1].
Clearance mechanisms for
pulmonary edema
It is important to study mechanisms involved in airspace
fluid clearance in patients with pulmonary edema. Indeed,
the lung’s ability to clear this pulmonary edema correlates
with patient survival and clinical parameters, such as
length of ventilation and O2 requirements, whether the
Table 1. Mechanisms of pulmonary edema
Increased
transvascular Increased
pressure permeability
Cardiogenic pulmonary edema ++++
Reexpansion pulmonary edema ++++ ++
Neonatal respiratory
distress syndrome ++ ++++
Neurogenic pulmonary edema ++++ ++++
High-altitude pulmonary ++++ ++
edema
Acute lung injury/acute
respiratory distress
syndrome ++++
patients have CHF-induced or ARDS-induced pulmonary
edema [2,3]. Alveolar fluid clearance (AFC) arises from
the lung’s distal lung epithelia actively transporting
Na+ with Clÿ and water following. Humans [4] have
AFC rates of ;25%/h [2]. To transport Na+ with Clÿ
and water following, cells must have Na+ permeant ion
channels on the apical membrane, Na+/K+ ATPase in
the basolateral membrane, and intercellular tight junc-
tions. Under normal conditions, the activity of Na+ per-
meant ion channels on the apical membrane represents
the rate-limiting step in lung epithelial Na+ transport.
However, under some circumstances when active Na+
transport is increased there is also a commensurate in-
crease in Na+/K+ ATPase activity [5,6].
Inadequate or abnormal active Na+ transport by the respi-
ratory epithelium has been shown to play a pathogenic role
in the initiation of two lung disorders characterized by
airspace edema.
The lungs of the newborn are filled with a protein-poor
fluid that had been actively secreted into the developing
lungs’ airspaces, part of the essential processes involved
in normal fetal lung development. Although this fluid is
not, strictly speaking, pulmonary edema, this airspace fluid
must be cleared by the epithelia’s active transepithelial
Na+ transport. As discussed elsewhere [7•], infants who
are born prematurely frequently have immature epithelial
Na+ transport, and the resultant impairment of the clear-
ance of this fetal lung liquid, combined with immaturity of
the surfactant system, are the two factors that initiate the
neonatal respiratory distress syndrome.
High-altitude pulmonary edema is initiated by an exces-
sive increase in pulmonary microvasculature pressure, al-
though it is debated whether there is an unequal
pulmonary vasoconstriction with resultant overperfusion
of remaining lung microvessels or an abnormal vasocon-
striction of the pulmonary venules. This initial noninflam-
matory leakage of fluid across the alveolar–capillary
membrane is followed by a secondary inflammatory

reaction promoting an increase in permeability. Recently,
it has been observed that human respiratory epithelial
Na+ transport decreases in response to the decreased
PO2 at high altitude [8,9]. In addition it has been shown
that salmeterol, which both alters vascular tone and
increases Na+ transport, diminishes the frequency of
high-altitude pulmonary edema [10]. Taken together
these observations provide the rationale for the hypothesis
that abnormal or defective lung epithelial Na+ transport
may be involved in the pathogenesis of high-altitude
pulmonary edema.
Therapy for pulmonary edema
Therapeutic strategies for pulmonary edema can be sim-
plified to four core principles, regardless of the disease
that is responsible for the increased lung water content.
Reversal of hypoxaemia
The first step is to reverse the hypoxaemia. If the pul-
monary edema is mild and predominately interstitial in
nature, then increasing the FIO2 will be effective in cor-
recting the low ventilation to perfusion (V/Q) ratios
(0 < V/Q < 1) arising from airway dysfunction secondary
to excess fluid within the bronchovascular sheaths and re-
flex vagal stimulation. Most patients in acute pulmonary
edema, however, have significant airspace pulmonary ede-
ma and the hypoxaemia occurs secondary to shunt, which
by definition is V/Q = 0. In this case one must increase
transpulmonary pressures to hold the lung at a higher vol-
ume and recruit lung units and thus decrease the amount
of shunt.
Reduction of the rate of fluid filtration
The second step is to reduce the rate of fluid filtration in-
to the lung. Treating the disorder that is responsible for
the pulmonary edema is the first priority. In CHF, for ex-
ample, we would improve cardiac contractility; reduce
preload; relieve anxiety (e.g., morphine), which will re-
duce both preload and afterload; decrease plasma volumes
and left atrial pressure and increase plasma colloid osmotic
pressures (e.g., administration of diuretics); decrease sys-
temic or pulmonary vascular pressures or both using vaso-
dilators; and reduce excessive salt and water intake. Such
measures are helpful in reducing the microvascular pres-
sures in the lung regardless of whether the cause of the
edema is haemodynamic or altered vascular permeability.
Diuretics, such as furosemide, are beneficial in pulmonary
edema because of their vascular effect of increasing sys-
temic venous capacitance and not because of the induced
diuresis. Since the lung represents only 1% of the total
body weight, even a 3-L diuresis would only remove
30 mL from the lungs, with the remaining fluid coming
from the remainder of the body. This 30 mL is trivial com-
pared with the liters of fluid present in the airspaces of
adult patients with florid alveolar edema. Improvement
Pulmonary edema O’Brodovich 383
in the patient’s status is usually seen within a few minutes
of administering the diuretic and hence prior to the diure-
sis. Adding to this argument is the fact that furosemide is
helpful even in anuric patients.
In high-permeability pulmonary edema, our goal is to re-
store the permeability of the alveolar – capillary mem-
brane to normal levels. Regrettably, there is no proven
way to modulate alveolar – capillary membrane permeabil-
ity, although low-dose corticosteroids [11] or activated
protein C in the subset of ARDS patients with sepsis
[12] have been beneficial to some degree in altering
the course of the overall disease.
Minimization of treated-related lung damage
The third step is to prevent or minimize treatment-related
damage to the lung, whether this occurs through the in-
halation of excessively high concentrations of oxygen or
the suboptimal use of mechanical ventilation and overdis-
tension of the lung, which induces damage to the lung’s
epithelium and endothelium. Attention to treatment of
the underlying condition combined with excellent sup-
portive care using lung-protective ventilatory strategies
to minimize treatment-related lung damage have contrib-
uted to successful clinical outcomes [13].
Augment the rate of clearance of airspace fluid
The lung’s ability to actively clear this pulmonary edema
correlates with patient survival and clinical parameters,
such as length of ventilation and O2 requirements, whether
the patient has CHF-induced or ARDS-induced pulmo-
nary edema [2,3]. Only 75% of patients with CHF have
demonstrable AFC and only ;40% achieve maximal
AFC rates [2]. It is more severe for patients with ARDS,
as fewer than 15% of these patients achieve maximal AFC
rates [3]. AFC is impaired more often in men and during
sepsis [3]. It is unknown why some patients cannot clear
edema fluid nor how to increase the AFC in a patient.
Although animal studies show that exogenous catechol-
amines augment AFC [5,14], patient studies have not
shown a correlation between the levels of circulating cat-
echolamines and AFC [2,3]. Other agents (e.g., growth
factors, cytokines, and steroids) increase AFC in the nor-
mal lung [5] but their effect on AFC in patients is un-
known. To the best of my knowledge there are no
therapeutic agents that have been proven in clinical trials
to enhance the AFC in patients with pulmonary edema.
Conclusion
Our laboratory has recently discovered [6] that pulmonary
edema fluid induces Na+ and fluid absorption by distal
lung epithelium. The effect of the edema fluid is both
time dependent and dose dependent and the causative
factors within the edema fluid are either proteins or re-
quire intact proteins to exert their effect. As a result of
the past several years of work involving a whole animal,
384 Pulmonology
cellular, molecular, and genetic approach we have now
discovered a protein complex that is responsible, at least
in part, for this effect. This work, now submitted for pub-
lication, offers the possibility of a new therapy for pulmo-
nary edema and other disorders with fluid-filled airspaces
such as the neonatal respiratory distress syndrome. If the
effect can be blocked, this finding has implications for
other diseases, such as cystic fibrosis and systemic hyper-
tension, which are characterized by abnormally increased
epithelial Na+ transport.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
• of special interest
•• of outstanding interest
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mott R and Bush A, editors. Kendig’s disorders of the respiratory tract in chil-
dren, 7th edition. Philadelphia, PA: Elsevier Science; in press.
2 Verghese GM, Ware LB, Matthay BA, Matthay MA. Alveolar epithelial fluid
transport and the resolution of clinically severe hydrostatic pulmonary edema.
J Appl Physiol 1999; 87:1301— —1312.
3 Ware LB, Matthay MA. Alveolar fluid clearance is impaired in the majority of
patients with acute lung injury and the acute respiratory distress syndrome.
Am J Respir Crit Care Med 2001; 163:1383.
4 Matthay MA, Wiener-Kronish JP. Intact epithelial barrier function is critical for
the resolution of alveolar edema in man. Am Rev Respir Dis 1990; 142:
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5 Matthay MA, Folkesson HG, Clerici C. Lung epithelial fluid transport and the
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6 Rafii B, Gillie DJ, Sulowski C, et al. Pulmonary oedema fluid induces non-a-
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iol 2002; 544:537— —548.
7 O’Brodovich H. Deficient Na + channel expression in newborn respira-
• tory distress syndrome. Pediatr Pulmonol 2004; 26(supplement):141— —
142.
This paper provides a review of the evidence indicating that immature (inadequate)
alveolar epithelial Na+ transport is one of the two factors, the other being relative
surfactant deficiency, that causes the respiratory distress syndrome in prematurely
born infants.
8 Mason NP, Petersen M, Melot C, et al. Serial changes in nasal potential dif-
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9 Mairbaurl H, Schwobel F, Hoschele S, et al. Altered ion transporter ex-
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